Research published in the July 5 issue of Neurology, the medical journal of the American Academy of Neurology, found an association between fluctuating levels of cholesterol and triglycerides in older adults and a higher risk of Alzheimer’s disease and related dementias (AD/ADRD) when compared to people with steady levels.

Moser ED, Manemann SM, Larson NB, et al. Association between fluctuations in blood lipid levels over time with incident alzheimer disease and alzheimer disease related dementias. Neurology. Published online July 5, 2023.

 

With more than 6 million Americans (of all ages) living with Alzheimer's—and an estimated 13.2 million older adults set to have AD/ADRD by 2050—these findings come at a time when prevention strategies are urgently needed, the authors state.

Alzheimer's Disease Facts and Figures. Alzheimer's Association.

What is alzheimer’s disease and related dementias. ASPE.

 

 

The study’s author, Suzette J. Bielinski, PhD of the Mayo Clinic in Rochester, Minnesota, told Newswise, “Routine screenings for cholesterol and triglyceride levels are commonly done as part of standard medical care.” She went on to say that fluctuations over time could not only potentially help healthcare providers determine who is at greater risk for dementia but uncover the mechanisms behind the development of dementia. In short, this research could help “determine whether leveling out these fluctuations could play a role in reducing dementia risk,” Dr. Bielinski continued. 

 

The study’s design & findings

 

The team selected a final cohort of 11,571 participants out of data from the Rochester Epidemiology Program (REP)—all of whom were residents of Olmsted County, Minnesota, over 60 (average age 71) without an AD/ADRD diagnosis. 

Only subjects with three or more lipid measurements—including total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C), or high-density lipoprotein cholesterol (HDL-C)—in the prior five years were included in the study. The subjects’ latest lipid values were taken prior to January 1, 2006. The authors note that most previous studies only examined lipid levels at a single point in time, vs changing levels occurring over time regardless of mean lipid levels. 

The authors looked at “lipid variation” as any change in the subjects’ lipid levels over time, whether an increase or decrease. “Associations between lipid variation quintiles and incident AD/ADRD were assessed using Cox proportional hazards regression,” they clarified. 

It is worth noting that the researchers did not differentiate between the types of dementia, so the associated risks refer to AD/ADRD. 

The researchers put the participants into five groups—based on their measurements. The lowest group had the least variation over time, and the highest group had the most variation, with some level of variation in between. The participants were followed through 2018, and watched for incidents of AD/ADRD, with an average follow-up of 12.9 years. 

The participants included in the study were more likely to be on treatment (50% vs 6% of excluded persons) at baseline and within the five years prior to baseline (67% vs 11% of the excluded persons).

Moreover, the authors write, “Compared to persons excluded, persons included were younger (mean age 71 vs 73 years)...and less likely to be female (54% vs 59%),” the authors write. The participants included were also more likely to have a history of stroke (13% vs 9%), myocardial infarction (7% vs 2%), diabetes (35% vs 13%), or cancer (22% vs 17%).”

In addition, persons included in the analysis were more likely to be on lipid-lowering treatment at baseline (50% vs 6%) and within the five years prior to baseline (67% vs 11%) than persons excluded.

The researchers found that over a 10-year average period, 2,473 (or 21%) of all participants developed incident AD/ADRD. Dr. Bielinski told MDLinx, “We found that those patients with the greatest fluctuations in total cholesterol and triglycerides were at higher risk for developing dementia. However, total cholesterol is made up of different types of cholesterol, and the relationship of these types and dementia is unknown.”

Participants in the highest variation group saw a 19% increased risk of AD/ADRD compared to those in the lowest variation group. Out of 2,311 people in the highest group, 515 developed dementia. In the lowest group of people, 483 people developed it. 

Regarding triglycerides levels, participants in the highest group had a 23% increased risk of AD/ADRD. They also found that only those in the highest quintile of triglyceride variability had the greatest association with AD/ADRD risk among those older than 70 years. “It may be that fluctuation in triglycerides is related to early stages of dementia and changes in behavior,” the researchers conject. 

Regarding lipid-lowering medication and risk, the researchers say there were no statistically significant interactions for either sex.

The authors say that while the mechanism behind AD/ADRD risk and lipid fluctuation isn’t fully understood, they offer a potential explanation: endothelial dysfunction, which may be an early marker for atherosclerosis. “Increased levels of serum markers related to endothelial dysfunction have also been shown to increase the risk of cognitive impairment and lower cerebral blood flow, which may increase the risk of incident AD/ADRD in later life,” the authors write. “Moreover, atherosclerosis has been found to increase the risk of Alzheimer’s disease. Total cholesterol variation may also lead to plaque instability, increasing the risk of cerebrovascular damage potentially contributing to incident AD/ADRD.”

Variations in LDL-C and HDL-C were not linked to an increased risk of AD/ADRD. Another theory? This lack of association could be due to “decreased sensitivity of these lipid profiles to early stages of dementia, diet, and other factors related to aging and frailty,” the authors posit.

 

What does this mean for healthcare providers?

 

According to Kenneth J. Perry, MD, FACEP, medical director at Moncks Corner Medical Center in Moncks Corner, SC, the study leaves a lot of room for additional research. However, Dr. Perry adds, the research may also direct HCPs to more closely—and more frequently—monitor responses to lipid-reducing medications, which patients are typically on for an extended period of time. “It also will help direct the conversation with the patients,” Dr. Perry says. 

“It is easy to tell a patient that being compliant with medications is important, but many times this is difficult to sell. This study can be extrapolated to state that medication compliance may lead to a more stable cholesterol and triglyceride levels in the blood. This allows for physicians to link direct health outcomes with taking medications correctly,” Dr. Perry says. 

So, what could potentially come next? Dr. Bielinski tells MDLinx that since “it is unknown if cholesterol fluctuations are a marker of dementia (i.e., a consequence of early disease) or a risk factor for dementia….additional research is needed to determine the utility of cholesterol fluctuations in clinical management.”

Lastly, she makes a note of another area worth watching: “The electronic health record contains longitudinal data for a variety of routinely measured biomarkers. Understanding if these data could be repurposed to improve the care of patients is an exciting area of research.”